There is now good evidence from model organisms that the pace of aging can be regulated1. Longevity regulatory genes have been identified in many eukaryotes, including rodents, flies, nematode worms and even single-celled organisms such as baker's yeast (reviewed in2,3). These genes appear to be part of an evolutionarily conserved longevity pathway that evolved to promote survival in response to deteriorating environmental conditions1,4. The yeast S. cerevisiae has proven a particularly useful model in which to study cell autonomous pathways of longevity regulation2. In this organism, replicative lifespan is defined as the number of daughter cells an individual mother cell produces before dying. Yeast lifespan extension is governed by PNC1, a calorie restriction (CR)—and stress-responsive gene that depletes nicotinamide, a potent inhibitor of the longevity protein Sir2. Both PNC1 and SIR2 are required for lifespan extension by CR or mild stress5,6 and additional copies of these genes extend lifespan 30-70%5-7. Based on these results we proposed that CR may confer health benefits in a variety of species because it is a mild stress that induces a sirtuin-mediated organismal defense response6.
Sir2, a histone deacetylase (HDAC), is the founding member of the sirtuin deacetylase family, which is characterized by a requirement for NAD+ as a co-substrate8-13. SIR2 was originally identified as a gene required for the formation of transcriptionally silent heterochromatin at yeast mating-type loci14. Subsequent studies have shown that Sir2 suppresses recombination between repetitive DNA sequences at ribosomal RNA genes (rDNA)15-17. Sir2 has also been implicated in the partitioning of carbonylated proteins to yeast mother cells during budding18. Studies in C. elegans, mammalian cells, and the single-celled parasite Leishmania, indicate that the survival and longevity functions of sirtuins are conserved19-22. In C. elegans additional copies of sir-2.1 extend lifespan by 50% via the insulin/IGF-1 signalling pathway, the same pathway recently shown to regulate lifespan in rodents23-25.